VISTA Regulates the Development of Protective Antitumor Immunity
Isabelle Le Mercier, Wenna Chen, Janet L Lines, Maria Day, Jiannan Li, Petra Sergent, Randolph J Noelle, Li Wang, Isabelle Le Mercier, Wenna Chen, Janet L Lines, Maria Day, Jiannan Li, Petra Sergent, Randolph J Noelle, Li Wang
Abstract
V-domain Ig suppressor of T-cell activation (VISTA) is a novel negative checkpoint ligand that is homologous to PD-L1 and suppresses T-cell activation. This study demonstrates the multiple mechanisms whereby VISTA relieves negative regulation by hematopoietic cells and enhances protective antitumor immunity. VISTA is highly expressed on myeloid cells and Foxp3(+)CD4(+) regulatory cells, but not on tumor cells within the tumor microenvironment (TME). VISTA monoclonal antibody (mAb) treatment increased the number of tumor-specific T cells in the periphery and enhanced the infiltration, proliferation, and effector function of tumor-reactive T cells within the TME. VISTA blockade altered the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells within the tumor microenvironment. In addition, VISTA blockade impaired the suppressive function and reduced the emergence of tumor-specific Foxp3(+)CD4(+) regulatory T cells. Consequently, VISTA mAb administration as a monotherapy significantly suppressed the growth of both transplantable and inducible melanoma. Initial studies explored a combinatorial regimen using VISTA blockade and a peptide-based cancer vaccine with TLR agonists as adjuvants. VISTA blockade synergized with the vaccine to effectively impair the growth of established tumors. Our study therefore establishes a foundation for designing VISTA-targeted approaches either as a monotherapy or in combination with additional immune-targeted strategies for cancer immunotherapy.
Conflict of interest statement
The authors have no additional financial interests.
Conflicts of interest: The authors RJN and LW are involved with ImmuNext Inc and receive financial support for the development of anti-VISTA for immunotherapy.
©2014 AACR.
Figures
![Figure 1. VISTA monoclonal antibody (mab) treatment…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4116689/bin/nihms565494f1.jpg)
![Figure 2. Effects of VISTA mab treatment…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4116689/bin/nihms565494f2.jpg)
![Figure 3. Effects of VISTA mab treatment…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4116689/bin/nihms565494f3.jpg)
![Figure 4. VISTA regulates the suppressive function…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4116689/bin/nihms565494f4.jpg)
![Figure 5. VISTA monoclonal antibody treatment suppressed…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4116689/bin/nihms565494f5.jpg)
![Figure 6. VISTA monoclonal antibody synergized with…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4116689/bin/nihms565494f6.jpg)
Source: PubMed